The competing renewal of this Program Project builds on important research findings from the initial funding period that advanced understanding of the intra-neuronal processing of the amyloid precursor proteins (APP) to generate alphabeta peptides, including a formic acid soluble pool of Abeta, and the role of human neuron derived alpha beta in the induction of neuron degeneration of and other pathologies found in the Alzheimer's disease (AD) brain. Based on their data, the investigators in the competing renewal application view the accumulation of extracellular Abeta deposits as necessary, but not sufficient to induce neurons to degenerate in AD. Provocative data on the intra-neuronal generation of amyloidogenic Abeta1-42 in vitro in human neuron-like NT2N cells and the dramatic augmentation of neuron death by traumatic brain injury (TBI) in transgenic mice prior to the formation of Alphabeta deposits in these mice are reported here, and this has led the investigators to propose a novel "two hit" hypothesis to explain how Abeta could compromise the viability of neurons in AD. Specifically, they propose that neurons have a latent vulnerability to the toxic effects of high concentrations of amyloidogenic alphabeta (the "first hit"), but this vulnerability only becomes manifest when these neurons are subjected to a second perturbation (i.e. the "second hit") such as TBI or cellular stress. Moreover, based on studies from the previous funding period of this Program Project, it is reasonable to consider the intra-neuronal milieu as the site wherein the "first hit" initially occurs. To test this hypothesis, the investigators use complementary research strategies to pursue 4 separate Projects: 1) "Biosynthesis And Processing Of Abeta In NT2N Cells" (R.W. Doms); 2) "Regulation of Intra-neuronal Abeta In Vitro" (V.M.-Y. Lee); 3) "Signal Transduction of APP Secretion in NT2N Cells" (B.A. Wolf); 4) "Traumatic Brain Injury and Alzheimer's Disease" (J.Q. Trojanowski). With the support of an Administrative and a Neuroscience Core, the investigators of this Program Project will determine how the insidious, age-dependent accumulation of intra-neuronal Abeta ("first hit") becomes toxic to selectively vulnerable neurons following the exposure of these neurons to another insult (i.e. the "second hit"), and the accomplishment of these studies is expected to have implications of understanding and treating AD.